"We have studied the role of the RB tumor suppressor pathway in human cancer focusing primarily on the model of lung cancer. We have generated a colony of mice (using different mouse strain backgrounds) that are double-heterozygote for RB/p53 null alleles. Each of these mice develops a spectrum of endocrine tumors that overlap with the MEN1 and MEN2 human syndromes. In addition, we have backcrossed these RB/p53 mutant alleles x 4 into the A/J murine strain that is susceptible to lung tumors. These mice are now beginning to develop a high frequency of lung tumors and we will analyze these tumors morphologically and biologically to determine the effect of RB versus p16 inactivation as the initial genetic hit. These mice also develop a high frequency of endocrine thyroid, pituitary, and pancreatic tumors and we will study the genetic basis of how RB inactivation facilitates the initiation or progression. We have also studied the functional properties of different RB mutant alleles that were identified in the germline of many different families with the phenotype of incomplete penetrance of familial retinoblastoma. In contrast to all previously identified RB mutations, we have demonstrated that these low penetrant alleles encode mutant proteins that retain several parameters of wildtype function. We will use these unique cDNA clones to study the molecular basis for low penetrance and to define more precisely tumor suppressor activities within the RB product."